In recent years, a variety of methods and devices have been disclosed for the administration of various beneficial agents, such as drugs or medicaments, to the body of a living being. For example, the agent may be dissolved in a fluid which is compatible with body tissues and body fluids and then administered to the living being by means of an intravenous tube. Alternatively, the agent in solution may be administered by means of an infusion pump. There are a number of patents which teach various types of infusion pumps. See, for example, U.S. Pat. No. 4,190,048, which discloses an apparatus having a reservoir which is implanted in the body of a living being and a pump which also is implanted. The pump can be refilled by injecting infusate through the skin of the patient, through a pump septum and into the chamber inside the apparatus.
Also well known are a number of devices which can be implanted inside the body of the living being and are constructed such that the beneficial agent can diffuse out of the device. For example, U.S. Pat. No. 3,279,996, issued to Long et al., discloses a method and means for the controlled release of a therapeutic agent into a living organism by implanting within the body of that organism a capsule formed of silicone rubber and containing a therapeutic agent soluble in and capable of diffusing through the rubber to its outer surface at a constant rate. Another patent, U.S. Pat. No. 3,845,770, issued to Theeuwes et al., is directed to an osmotic device for the controlled release of an agent which comprises a semi-permeable membrane that surrounds a compartment which contains the agent. The wall is permeable to an external body fluid but impermeable to the agent and has a passageway for delivering the agent to the body. To release the agent, fluid is imbibed through the wall into the compartment to produce a solution of the agent. That solution is dispensed through the passageway at a rate controlled by the permeability of the wall and the osmotic pressure gradient across the wall of the device.
Despite these and various other systems and devices for releasing beneficial agents, certain problems have remained. One problem is that certain beneficial agents, especially high molecular weight agents, such as some proteins, are unstable, insoluble or cannot be solubilized in body fluids or other aqueous-based solvents. As a result, when they are placed in a slow release delivery device and come into contact with body fluids or they are added to a solution for purposes of intravenous administration, they have a tendency to transform into insoluble aggregates.
Attempts have been made to solve this problem. For example, U.S. Pat. No. 4,439,181, issued to Blackshear, discloses a method for preventing the precipitation of solubilized insulin within an infusion pump-type of delivery system that depends on the fluidity of the insulin solution for proper function. Specifically, Blackshear discloses stabilizing the insulin by adding an effective amount of a polyol, such as glycerol, to the solution.
Similarly, U.S. Pat. No. 4,306,553, issued to Dorman, teaches adding specific detergents in low concentrations to an insulin solution to maintain the solution's fluidity.
Although the teachings of these two patents may be helpful in certain situations, further methods for stabilizing polypeptides are sought.